Inhibitors of HIV-1 integrase (IN) inhibitors represent the most recent anti-AIDS drugs. Merck's raltegravir (RAL) (October 2007) and Gilead's elvitegravir (EVG) (August 2012) were the first two IN inhibitors to be approved by the FDA. These agents are members of a class of drugs called IN strand transfer inhibitors (INSTIs), due to their ability to preferentially block the enzyme's strand transfer (ST) reaction as compared to the enzymes 3'-processing (3'-P) reaction. Treatment with RAL and EVG selects for resistant forms of HIV and there is considerable cross-resistance to these two drugs. GlaxoSmithKline's dolutegravir (DTG) was approved by the FDA in August of 2013 as a 2nd-generation INSTI having improved efficacies against RAL and EVG-resistant strains of HIV. However, DTG also selects for resistant strains of HIV, emphasizing the need for continued development of agents that can overcome resistant strains of IN, including the emerging DTG-resistant strains. Utilizing my laboratory's design and synthetic capabilities, we have teamed with pharmacologists (Dr. Yves Pommier, NCI), virologists (Dr. Hughes, NCI) and structural biologists (Dr. Cherepanov, London Research Institute) to develop new IN inhibitors. These efforts have resulted in the discovery of 1-hydroxy-1,8-naphthyridin-2H-one-3-carboxamides, which potently inhibit wild-type (WT) IN in biochemical assays and show good anti-viral efficacies in single-round infection assays of HIV-1 infectivity. Importantly, members of this series retain good anti-viral potency against RAL-resistant mutants in the latter assays. More recently, we have found by introducing modifications to the 6-position of the 1-hydroxy-2-oxo-1, 8-naphthyridine scaffold, that we are able to obtain INSTIs with low nanomolar potencies against an entire panel of viruses, including the canonical INSTI-resistant IN variants. The compounds are characterized by low cytotoxicities, which in several cases, results in selectivity indices (CC50/EC50) of greater than 10,000. In collaboration with Dr. Cherepanov, we have obtained co-crystal structures of our lead inhibitors bound to the prototype foamy virus (PFV) intasome (tetrameric integrase with substrate DNA). This data clarifies the structural basis of the compounds' actions and provides key insights that may be useful in further optimizing biochemical efficacies. Along with IN, the HIV-1 polymerase (Pol) and RNase H domains of reverse transcriptate (RT), belong to a superfamily of polynucleotidyl transferases that share a similar catalytic mechanism involving two divalent metal ions. We have found that members of our recent INSTIs inhibit both the Pol and RNase H activities of RT. Work is in progress to further develop inhibitors directed at these targets.